APJ Receptor

Two hydroxypyridinone-containing actinide decorporation providers, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Animal Efficacy Rule (15), which allows for authorization of a new drug based on (1) effectiveness data from more than one animal varieties, and (2) security data from animals and normal human being volunteers. Effectiveness would therefore only become shown in animals because controlled medical tests, in which actinides were given to humans for the sole purpose of decorporation tests, would be unethical. There is currently no precedent for the authorization of a new radionuclide decorporation agent under the Animal Efficacy Rule even though FDA issued a guidance document that details their current thinking on the topic (14). The superior decorporation effectiveness of 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) in PR-171 several animal varieties (4, 5, 10, 12), the pharmacokinetic profile of these ligands in Sprague-Dawley rats (17), and the results from preclinical security studies carried out under good laboratory practice (GLP) where Sprague-Dawley rats were orally given these ligands for 28 days (12) have all been previously explained. Herein we discuss additional rodent effectiveness and preclinical security results that have arisen as these decorporation providers progress down the drug development pathway. Specifically, we statement (1) that 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) chelate Am and Pu inside a dose-responsive manner after parenteral and oral administration in female Swiss-Webster mice with superior effectiveness when compared to control mice that were given Ca-DTPA, (2) that both ligands are not genotoxic in the FDA-required GLP genetic toxicology bacterial reverse mutation Ames assay and the chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and (3) the maximum tolerated dose (MTD) safety results in male Sprague-Dawley rats after 7 consecutive days of oral administration. The results of these studies add to the growing body of evidence that 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) both have remarkable decorporation effectiveness properties and encouraging safety toxicology profiles. MATERIALS AND METHODS General All chemicals were from commercial suppliers and used as received. The test content articles 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) were prepared by Albany Molecular Study, Inc. (Albany, NY), Synthetech, Inc. (Albany, OR), Starks Associates (Buffalo, NY) or Ash Steven’s Inc. (Detroit, MI), as explained previously (12). The general procedures for animal care and housing were conducted in accordance with the National Study Council for the Care and Use of Laboratory Animals and the Animal Welfare Requirements (18). All methods and protocols used in the explained studies were reviewed and authorized by the Institutional Animal Care and Use Committees of Lawrence Berkeley National Laboratory or SRI International, and were performed in AAALAC accredited facilities. Efficacy Studies in Mice Test article solutions were prepared such that the selected dose [ranging from 0.03 to 500 mol/kg for CaNa3-DTPA, 0.01 to 200 mol/kg for 3,4,3-LI(1,2-HOPO) and 0.01 to 500 mol/kg for 5-LIO(Me-3,2-HOPO)] was contained PR-171 in 0.5 ml of 0.14 NaCl. The pH of the dosing solutions were modified to 7.4C8.4 with sodium hydroxide. All solutions Rabbit polyclonal to AFF2. were filter-sterilized (0.22 m) prior to administration. Multiple groups of five female Swiss-Webster mice (13C14 weeks older, 26.1C33.0 g; Simonsen Laboratories, Gilroy, CA) were used for PR-171 each experiment. Each group of mice was housed collectively inside a plastic stock cage lined having a 0.5 cm coating of highly absorbent low-ash pelleted cellulose bedding (ALPHA-dri?) for separation of urine and feces. All mice were given water and food until PR-171 the start of the study. Some groups of mice were fasted for 16 h prior to treatment, while others were managed under normal diet for the duration of the study. Under isoflurane anesthesia, 0.2 ml of an actinide solution was injected intravenously (i.v.) into the lateral tail vein of each animal. Radioactivities and metallic people of the actinide solutions in 8 msodium citrate were 238Pu (0.74 kBq, PR-171 1.2 ng) or 241Am (0.43 kBq, 3.7 ng in injection experiments; 0.65 kBq, 5.5 ng in oral experiments); ligands were given by intraperitoneal (i.p.) injection to normally fed mice or orally (gastric intubation, po) to fasted mice 1 h after the actinide administration. Food was provided to the fasted mice 4 h after the actinide injection. All animals were euthanized 24 h after the actinide injection. Details of sample collection, preparation, radioactivity measurements and data reduction have been published previously (19, 20). All individual samples were mixed with Ultimagold (Perkin Elmer Corporation, Shelton, CT) for detection of the radiotracers, 238Pu and 241Am, by liquid scintillation counting (Packard Tri-Carb model B4430; Perkin Elmer). Metabolic.